Orexin In the News

That
lucky friend of yours — the one who barely gains weight when eating the same
things you eat, even though your waistline expands — might have a hormone called
orexin to thank.

A new study shows that mice deficient in orexin, which is produced in the brain,
gained more weight when fed the same high-fat diet as mice that weren't
deficient in the hormone.

Supplementing this hormone may be one way to help people lose weight, the
researchers suggested, though the new findings are preliminary.

The hormone helps stave off weight gain because it's involved in the body's
production of brown fat, which burns calories rather than storing them as white
fat does, the study showed.

"Without orexin, mice are permanently programmed to be obese.
With it, brown fat
is activated and they burn more calories," said study researcher Devanjan
Sikder, an assistant professor in Sanford-Burnham Research Institute, in Lake
Nona, Fla.

The study is published today (Oct. 4) in the journal Cell Metabolism.

Orexin staves off weight gain, boosts metabolism

The researchers compared normal mice with mice engineered to lack orexin. When
fed a high-fat diet for six weeks, the orexin-deficient mice increased their
body weight by 45 percent, while the normal mice plumped up by just 15 percent.

This increased weight gain happened even though the orexin-deficient mice ate
less of their food than the normal mice did, the study showed.

The researchers hypothesized that orexin-deficient mice were somehow expending
less energy. The found that after eating the high-fat diet, the normal mice's
metabolic rate rose 13.5 percent, while the orexin-deficient mice showed no such
increase in metabolism.

The researchers collected samples of brown fat from between the mice's shoulder
blades, and found that the brown fat of the orexin-deficient mice was immature
compared to that of the normal mice. For example, genes whose expression was
cranked up in the normal mice's brown fat were tamped down in the
orexin-deficient mice.

"Our study provides a possible reason why some people are overweight or obese
despite the fact that they don't overeat," Sikder said.

Orexin in people

Orexin deficiency is known to exist in people with narcolepsy, and previous
studies have linked low levels of orexin and obesity in people, the study said.

Measuring the activity of brown fat in people with orexin deficiencies could
show whether the same mechanism is at work in people, the researchers wrote.

However, because the hormone also seems to simulate wakefulness, supplementing
orexin could make it difficult to sleep, the researchers cautioned.

Brown
fat has been a hot topic in obesity research in recent years. So has a hormone
produced in the brain called orexin. Now scientists have linked these two
concepts in a theory that may lead to new weight-loss therapies.

Brown fat is a healthy substance that contains blood vessels and helps burn fat.
People who are obese are thought to have less-active brown fat. Orexin is a
hormone that is known to play a role in controlling appetite. In a paper
published Tuesday, scientists have shown that
orexin also activates brown fat to
burn calories.

The study used mice who were genetically engineered to lack orexin. These mice
were obese even though they ate less than other mice. When scientists looked at
the brown fat composition, they found that fat cells didn't develop properly
when the mice were embryos. That defect caused a lifelong predisposition to gain
weight.

The research supports the theory that obesity can have its roots in the fetal
environment and raises the stakes on understanding prenatal brown fat
development.

"Without orexin, mice are permanently programmed to be obese," the lead author
of the study, Dr. Devanjan Sikder of the Sanford-Burnham Medical Research
Institute in Orlando, Fla., said in a news release. "We're now taking the next
steps in determining how orexin -- or a chemical that has the same effect --
might be used in humans to therapeutically prevent or treat obesity."

The fat we typically think of as body fat is called white fat. But there's
another type -- known as brown fat -- that does more than just store fat. It
burns fat. Scientists used to think that brown fat disappeared after infancy,
but recent advances in imaging technology led to its rediscovery in adult
humans. Because brown fat is so full of blood vessels and mitochondria -- that's
what makes it brown -- it's very good at converting calories into energy, a
process that malfunctions in obesity.

In a study published Oct. 5 in Cell Metabolism, researchers at Sanford-Burnham
Medical Research Institute (Sanford-Burnham) discovered that
orexin, a hormone
produced in the brain, activates calorie-burning brown fat in mice. Orexin
deficiency is associated with obesity, suggesting that
orexin supplementation
could provide a new therapeutic approach for the treatment of obesity and other
metabolic disorders. Most current weight loss drugs are aimed at reducing a
person's appetite. An orexin-based therapy would represent a new class of
fat-fighting drugs -- one that focuses on peripheral fat-burning tissue rather
than the brain's appetite control center.

"Our study provides a possible reason why some people are overweight or obese
despite the fact that they don't overeat -- they might lack the orexin necessary
to activate brown fat and increase energy expenditure," explained Devanjan
Sikder, D.V.M, Ph.D., senior author of the study and assistant professor in
Sanford-Burnham's Diabetes and Obesity Research Center, located in Orlando's
Medical City at Lake Nona.

Since the best way to determine something's function is to see what happens when
it's missing, Dr. Sikder's team, which included postdoctoral researchers Dyan
Sellayah, Ph.D. and Preeti Bharaj, Ph.D., looked at mice genetically engineered
to lack orexin. These mice weighed more than their normal counterparts, but they
actually ate less, suggesting that
overconsumption was not the cause of their
obesity. Rather, the orexin-deficient mice lacked diet-induced thermogenesis
(heat production); in other words, when fed a high-fat diet, the mice failed to
dissipate the extra calories as heat the way that normal mice (and people) do.
Instead, they stored that energy as fat.

This finding prompted the team to look at the mice's brown fat -- a source of
thermogenesis. What they found is that brown fat in mice lacking orexin didn't
develop properly at the embryonic stage. This shortage had lasting effects on
energy expenditure and weight even in adulthood.

Taking the opposite approach, the researchers then gave the defective mice more
orexin. With the hormone present, brown fat developed properly before birth and
continued to be active into adulthood. What's more,
adding orexin to stem cells
in a laboratory dish caused them to differentiate (specialize) into brown fat
cells, creating more of this fat-burning engine.

"Without orexin, mice are permanently programmed to be obese. With it, brown fat
is activated and they burn more calories," said Dr. Sikder. "We're now taking
the next steps in determining how orexin -- or a chemical that has the same
effect -- might be used in humans to therapeutically prevent or treat obesity."

According to the Centers for Disease Control and Prevention, about one-third of
U.S. adults (33.8 percent) are obese. As a person becomes overweight or obese,
he or she is at increased risk for type 2 diabetes, coronary heart disease,
stroke, and certain cancers.